The invention is directed to antibacterial compounds that expand the repertoire of erythromycin-like antibiotics. More particularly, the invention concerns macrolide antibiotics containing an erythronolide nucleus modified at least at the substituent at C-13.
The increasing number of microbial strains that have acquired resistance to the currently available known antibiotic compounds is recognized as a dangerous threat to public health. As the use of such compounds has proliferated, so too has the need for expanding the options available to treat a wide variety of microbial-based conditions. The need for a larger choice of antimicrobial compounds extends beyond treatment of human infection and to a need to preserve food and other perishable commodities. New antibiotics can also be essential for resistant plants and animals as well as to provide resistance to materials that otherwise are subject to microbially caused corrosion.
Thus, there is a clear need for an expanded armament of compounds which can provide a multifaceted defense against unwanted microbial activity.
WO 98/09978 published Mar. 12, 1998 and incorporated herein by reference discloses modified forms of erythromycin which lack a cladinose residue at the 3-position and which are derivatized in various ways in positions 9-12 of the macrolide ring. Similarly, U.S. Pat. No. 5,750,510, issued May 12, 1998 and incorporated herein by reference, discloses modified erythromycin derivatives.
The naturally occurring erythromycins have the structure
wherein Rxe2x80x2 can be H or OH and Rxe2x80x3 can be H or CH3.
All of the compounds disclosed in the above-referenced patent documents contain an ethyl group at position 13 of the macrolide ring. The present inventors have found that alterations in the substituent at position 13 results in a large number of compounds with excellent antibacterial activity.
The invention is directed to erythronolide derivatives that contain modifications from the native structure. All of the compounds of the invention are modified at least at position 13.
Thus, in one aspect, the invention is directed to compounds of the formula 
or the 10,11-anhydro forms thereof; wherein
Ra is H or OH, preferably OH;
Rb is H or halogen;
Rc is H or a protecting group;
Rd is methyl; unsubstituted alkyl (3-10C); substituted alkyl (1-10C); substituted or unsubstituted alkenyl (2-10C); substituted or unsubstituted alkynyl (2-10C); substituted or unsubstituted aryl (4-14C); substituted or unsubstituted arylalkyl (5-20C); substituted or unsubstituted arylalkenyl (5-20C); substituted or unsubstituted arylalkynyl (5-20C); substituted or unsubstituted amidoarylalkyl (5-20C); substituted or unsubstituted amidoarylalkenyl (5-20C); or substituted or unsubstituted amidoarylalkynyl (5-20C);
Re is H or a protecting group or is mono- or disubstituted amino carbonyl;
Rf is H; substituted or unsubstituted alkyl (1-10C); substituted or unsubstituted alkenyl (1-10C); substituted or unsubstituted alkynyl (1-10C); substituted or unsubstituted aryl (4-14C); substituted or unsubstituted arylalkyl (5-20C); or ORf may be replaced by H;
one of Z and Y is H and the other is OH or protected OH, or is amino, mono- or dialkyl-amino, protected amino, or an aminoheterocycle or
Z and Y together are xe2x95x90O, xe2x95x90NOH or a derivatized oxime;
including any pharmaceutically acceptable salts thereof and any stereoisomeric forms and mixtures of stereoisomeric forms thereof.
In another aspect, the invention is directed to pharmaceutical or preservative compositions containing the compounds of formulas (1)-(3) and to methods to treat infectious diseases by administering these compounds or to preserve materials by providing them.
The compounds of the invention have antibiotic activity, but preferably are useful as semi-synthetic intermediates for forming 10, 11 anhydro forms of the compounds that are further converted to compounds having an erythronolide nucleus and having a ring between the C10 and C11 positions of the erythronolide nucleus as described in U.S. provisional patent application Ser. No. 60/140,175 filed Jun. 18, 1999 and No. 60/172,159 filed Dec. 17, 1999 and U.S. utility patent application Ser. No. 09/550,045 filed Apr. 14, 2000 entitled xe2x80x9cMacrolide Antiinfectivesxe2x80x9d, which are incorporated by reference.